Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies
Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies
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DOI：
10.1038/leu.2012.4
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发表时间：
2012-06-01
期刊：
影响因子：
11.4
通讯作者：
Fulda, S.
中科院分区：
文献类型：
--
作者：
Fulda, S.
对细胞凋亡的抗性是人类癌症的标志之一，并导致许多癌症对常用的治疗方法不敏感。凋亡抑制因子（Inhibitor of apoptosis，IAP）蛋白是一类抗凋亡蛋白家族，在细胞逃避凋亡过程中发挥重要作用，能够阻断凋亡信号通路，促进细胞存活。IAP蛋白的高表达在包括血液系统恶性肿瘤在内的多种癌症中观察到，并且与不良预后和患者预后不良相关。因此，IAP蛋白目前被认为是有希望的治疗分子靶点。事实上，在过去十年中，旨在中和IAP蛋白的药物发现方法已经导致产生小分子抑制剂或反义寡核苷酸，这些抑制剂或反义寡核苷酸在临床前研究中显示出体外和体内抗肿瘤活性。由于这些策略中的一些已经进入临床评估阶段，例如，在白血病中，对这种有前途的分子靶向策略的更新以干扰细胞凋亡途径具有广泛的兴趣。
Resistance to apoptosis is one of the hallmarks of human cancers and contributes to the insensitivity of many cancers to commonly used treatment approaches. Inhibitor of apoptosis (IAP) proteins, a family of anti-apoptotic proteins, have an important role in evasion of apoptosis, as they can both block apoptosis-signaling pathways and promote survival. High expression of IAP proteins is observed in multiple cancers, including hematological malignancies, and has been associated with unfavorable prognosis and poor patients' outcome. Therefore, IAP proteins are currently considered as promising molecular targets for therapy. Indeed, drug-discovery approaches over the last decade aiming at neutralizing IAP proteins have resulted in the generation of small-molecule inhibitors or antisense oligonucleotides that demonstrated in vitro and in vivo antitumor activities in preclinical studies. As some of these strategies have already entered the stage of clinical evaluation, for example, in leukemia, an update on this promising molecular-targeted strategy to interfere with apoptotic pathways is of broad interest.